Meloxicam emulgels for topical management of rheumatism: Formulation development, in vitro and in vivo characterization.

PURPOSE: The study designed, formulated and evaluated meloxicam emulgels as a potential alternative topical treatment option for rheumatism. METHODS: A 32 factorial design was employed to formulate nine preliminary meloxicam emulgels (Formulations F1 - F9). The influences of carbopol-934 and menthol as gelling agent and drug release enhancer, respectively, were correlated with four pharmaceutical properties of the formulated emulgels namely viscosity, spreadability, and cumulative drug release at one hour and at eight hours. Using the generated data and applying the Design Expert® modelling software, two optimized meloxicam emulgels (Formulations F10 and F11) were designed, formulated and evaluated. In vivo anti-inflammatory efficacy was conducted using carrageenan-induced rat paw oedema method. Drug release kinetics was modelled using DDSolver® dissolution software. RESULTS: All formulations were homogenous with no observable grittiness or phase separation. The optimized Formulations F10 and F11 had pH 6.5 and 6.4, viscosity of 23656 and 24524 mPa.s, spreadability of 9.9 and 9.5 cm, and drug content of 90.4% and 92.9%, respectively, all within optimal values. The cumulative percentage of drug released was 21.0% and 22.9% after one hour and 50.1% and 55.8% after eight hours for Formulations F10 and F11, respectively. Drug release kinetics exhibited Fickian diffusion best described by Korsmeyer-Peppas model. Paw volume inhibition by Formulation F11 at two and three hours after carrageenan injection was statistically significant (p < 0.05). CONCLUSION: The optimized meloxicam emulgels had high pharmaceutical quality and were pharmacologically active. Further optimization could potentially provide a safe and efficacious alternative treatment option for rheumatism.

Antihypertensive therapy and adequacy of blood pressure control among adult hypertensive diabetic patients with chronic kidney disease in a tertiary referral hospital.

Background: Tight blood pressure control retards the development of end-stage renal disease in hypertensive diabetic patients with chronic kidney disease. There is limited literature on blood pressure control among this patient population in a resource-limited setting. Research design and methods: A tertiary hospital-based cross-sectional study with 237 hypertensive diabetic patients with chronic kidney disease was conducted. A pre-tested questionnaire was used to assess patients' awareness of their ideal blood pressure. Data on blood pressure readings and antihypertensive therapies were abstracted into predesigned data collection forms and analyzed using STATA software version 13.0. Results: The participants' mean age was 61.8 ± 12.7 years and 106 (44.7%) patients were aware of the blood pressure targets. Adequate blood pressure control was found in 30.8%. Most (58.7%) were using ≥ 3 antihypertensive drug classes. Calcium channel blockers (51.1%), with principally amlodipine (26.2%) and nifedipine (24.1%), were the most preferred agents. Bivariate analysis showed enalapril (p = 0.009) and nifedipine (p = 0.022) being associated with adequate blood pressure control. However, nifedipine (AOR 2.79; 95% CI: 1.12-6.9, p = 0.028) and awareness of ideal blood pressure targets (AOR 4.57; 95% CI: 1.25-16.7, p = 0.022) were independent predictors of good control. Conclusion: Adequacy of blood pressure among hypertensive diabetic patients with chronic kidney disease is low and may be attributable to unawareness of its target level and using inappropriate therapy. Future studies should correlate level of blood pressure control with patient-, clinician-, and hospital-related factors.

Antischistosomal Activity of Pyrido[1,2-a]benzimidazole Derivatives and Correlation with Inhibition of ß-Hematin Formation.

The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit ß-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 µM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between ß-hematin inhibitory and antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most active compound in vivo showed 58.7 and 61.3% total and female worm burden reduction, respectively. Pharmacokinetic analysis suggested solubility-limited absorption and high hepatic clearance as possible contributors to the modest efficacy despite good in vitro activity. The PBIs evaluated in this report thus merit further optimization to improve their efficacy and to elucidate their possible mode of action.

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model.

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Computer-Aided Drug Discovery Approaches against the Tropical Infectious Diseases Malaria, Tuberculosis, Trypanosomiasis, and Leishmaniasis.

Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases. The research efforts have involved increased application of computational technologies in mainstream drug discovery programs at the hit identification, hit-to-lead, and lead optimization stages. This review highlights various computer-aided drug discovery approaches that have been utilized in efforts to identify novel antimalarial, antitubercular, antitrypanosomal, and antileishmanial agents. The focus is largely on developments over the past 5 years (2010-2014).

Design, Synthesis, and Antiplasmodial Activity of Hybrid Compounds Based on (2R,3S)-N-Benzoyl-3-phenylisoserine.

A series of hybrid compounds based on (2R,3S)-N-benzoyl-3-phenylisoserine, artemisinin, and quinoline moieties was synthesized and tested for in vitro antiplasmodial activity against erythrocytic stages of K1 and W2 strains of Plasmodium falciparum. Two hybrid compounds incorporating (2R,3S)-N-benzoyl-3-phenylisoserine and artemisinin scaffolds were 3- to 4-fold more active than dihydroartemisinin, with nanomolar IC50 values against Plasmodium falciparum K1 strain.